CN106243182B - Enoxolone-hydrogen sulfide donor reagent derivatives and its synthetic method and application - Google Patents
Enoxolone-hydrogen sulfide donor reagent derivatives and its synthetic method and application Download PDFInfo
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- CN106243182B CN106243182B CN201610621147.1A CN201610621147A CN106243182B CN 106243182 B CN106243182 B CN 106243182B CN 201610621147 A CN201610621147 A CN 201610621147A CN 106243182 B CN106243182 B CN 106243182B
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- compound
- hydrogen sulfide
- donor reagent
- sulfide donor
- alkali
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- 229910000037 hydrogen sulfide Inorganic materials 0.000 title claims abstract description 29
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 25
- 238000010189 synthetic method Methods 0.000 title abstract description 4
- 229940125904 compound 1 Drugs 0.000 claims abstract description 22
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 19
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 19
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002798 polar solvent Substances 0.000 claims abstract description 17
- 239000003513 alkali Substances 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims abstract description 8
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims abstract description 8
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims abstract description 8
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 87
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 238000001308 synthesis method Methods 0.000 claims description 21
- 239000000706 filtrate Substances 0.000 claims description 20
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 16
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 15
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- 229960003720 enoxolone Drugs 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- MPDGHEJMBKOTSU-WFJWTYAKSA-N (2s,4as,6as,6br,10s,12as)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid Chemical compound C12C(=O)C=C3C4C[C@@](C)(C(O)=O)CC[C@]4(C)CC[C@@]3(C)[C@]1(C)CCC1[C@]2(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-WFJWTYAKSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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Abstract
The invention discloses a kind of enoxolone-hydrogen sulfide donor reagent derivatives and its synthetic method and applications.The synthetic method of the derivative is：Extracting liquorice hypo acid, α, ω-two bromoalkane and alkali react in aprotic polar solvent, obtain compound 1；It takes compound 1, hydrogen sulfide donor reagent and alkali to react in aprotic polar solvent, obtains object crude product；Wherein, reaction carries out under conditions of being heated or not heated.Synthesis, which obtains the majority of compounds in derivative, has certain inhibitory activity to chronic myeloid leukemia cells K562, is expected to be used for corresponding anti-tumor drug and treats the preparation of the drug of chronic myelogenous leukemia.The obtained derivative that synthesizes has structure shown in the following general formula (I)：Wherein, n is 2~8；R isOr
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a glycyrrhetinic acid-hydrogen sulfide donor reagent derivative and a synthesis method and application thereof.
Background
Hydrogen sulfide is a new bioactive gas molecule that follows CO and NO, is an important role in supporting life, has irreplaceable physiological regulation in life activities, controls various intracellular signaling processes, and exerts active regulation. The current potential therapeutic applications of hydrogen sulfide mainly focus on the nervous and cardiovascular systems, such as treating hypertension, treating ischemic heart diseases, treating atherosclerosis, and reducing metabolism, preventing hypoxic injury, etc., in combination with non-steroidal anti-inflammatory drugs.
The hydrogen sulfide donor can hydrolyze under physiological conditions to spontaneously emit H2S or release of H by cysteine (GSH)2S, GSH can accept S sulfur atom of sulfide to form GSSH, and then generate H through catalysis of 3-mercaptopyruvate sulfur transferase (3-MST)2S。H2The research on the biological effect and the signal path mechanism of S reveals that the S serving as a signal molecule is involved in the cell signal transduction of a plurality of organs such as cardiovascular system, nervous system, circulatory system and the like, and has influence on a plurality of physiological processes in a body.
Glycyrrhetinic acid is the main pharmacological active substance of Glycyrrhrizae radix. In recent years, with the research on the pharmacological actions of glycyrrhetinic acid, the pharmacological actions of glycyrrhetinic acid are increasingly recognized, and the pharmacological actions include various pharmacological actions such as anti-tumor, anti-inflammatory, antivirus, cardiovascular disease treatment, immunoregulation, antioxidation and the like. The natural product is taken as a lead compound, structural modification is carried out on the natural product to introduce a pharmacophore with corresponding activity, and then pharmacological activity research in corresponding fields is carried out, so that the natural product becomes a research hotspot for research and development of new drugs.
At present, no related report on derivatives of glycyrrhetinic acid and hydrogen sulfide donor reagent connected through an alkane chain, and a synthetic method and application thereof is found.
Disclosure of Invention
The invention aims to solve the technical problem of providing glycyrrhetinic acid-hydrogen sulfide donor reagent derivatives with novel structures, and a synthesis method and application thereof.
The invention relates to a glycyrrhetinic acid-hydrogen sulfide donor reagent derivative with a structure shown in the following general formula (I) or a pharmaceutically acceptable salt thereof:
wherein,
n is 2-8;
r is
the synthesis method of the glycyrrhetinic acid-hydrogen sulfide donor reagent derivative comprises the steps of taking glycyrrhetinic acid, α, omega-dibromoalkane and alkali to react in an aprotic polar solvent to obtain a compound 1, and taking the compound 1, a hydrogen sulfide donor reagent and alkali to react in the aprotic polar solvent to obtain a target crude product, wherein the reaction is carried out under the condition of heating or not.
The more specific synthesis method comprises the following steps:
1) reacting glycyrrhetinic acid, α, omega-dibromoalkane and alkali in an aprotic polar solvent, removing the solvent from the obtained reactant, dispersing the residue in ethyl acetate, dichloromethane or diethyl ether, washing, drying with anhydrous sodium sulfate, filtering, collecting the filtrate, and concentrating the filtrate to obtain a compound 1;
2) taking the compound 1, a hydrogen sulfide donor reagent and alkali to react in an aprotic polar solvent, removing the solvent from the obtained reactant, dispersing the residue in ethyl acetate, dichloromethane or ether, washing, drying with anhydrous sodium sulfate, filtering, collecting the filtrate, and concentrating the filtrate to obtain a crude product of the target product.
In the above-mentioned specific synthesis method, in the step 1) and the step 2), the washing is preferably carried out by sequentially washing with hydrochloric acid, water and a saturated saline solution, or by sequentially washing with hydrochloric acid and a saturated saline solution.
The structural formula of the compound 1 synthesized in the synthesis method is as follows:
wherein n is 2-8.
The compound 1 synthesized in the above method is a crude product of the compound 1, and in order to improve the purity of the compound 1 and reduce the generation of more by-products in the subsequent reaction, the crude product of the compound 1 is preferably purified by silica gel thin layer chromatography or silica gel column chromatography and then used in the subsequent operation. When the method is used for silica gel thin-layer chromatography or silica gel column chromatography, the volume ratio of the silica gel thin-layer chromatography to the silica gel column chromatography is generally 2-10: 1 and eluting with an eluent consisting of Petroleum Ether (PE) and Ethyl Acetate (EA), collecting the eluent, and evaporating the eluent under reduced pressure to remove the solvent to obtain the purified target substance. The volume ratio of the petroleum ether and the ethyl acetate which form the eluent is preferably 2-5: 1.
the crude compound of formula (I) is obtained by the above process and can be purified by conventional purification methods to increase the purity of the compound of formula (I). Usually, silica gel thin layer chromatography or silica gel column chromatography is adopted for purification, and when the prepared crude target compound is subjected to silica gel thin layer chromatography or silica gel column chromatography, the volume ratio of the silica gel thin layer chromatography to the silica gel column chromatography is usually 2-10: 1 and eluting with an eluent consisting of Petroleum Ether (PE) and Ethyl Acetate (EA), collecting the eluent, and evaporating the eluent under reduced pressure to remove the solvent to obtain the purified target substance. The volume ratio of the petroleum ether and the ethyl acetate which form the eluent is preferably 2-5: 1.
in the synthesis method of the invention, the α, omega-dibromoalkane can be 1, 2-dibromoethane, 1, 3-dibromopropane, 1, 4-dibromobutane, 1, 5-dibromopentane, 1, 6-dibromohexane, 1, 7-dibromoheptane or 1, 8-dibromooctane.
In the synthesis method of the invention, the alkali can be potassium carbonate, triethylamine, sodium carbonate, sodium bicarbonate, potassium bicarbonate or cesium carbonate. When the base is selected to be cesium carbonate, higher yields can be obtained; preferably, the base is potassium carbonate, in view of cost and yield.
In the synthesis method of the invention, the aprotic polar solvent can be one or a combination of more than two of N, N-Dimethylformamide (DMF), toluene and pyridine, and when the aprotic polar solvent is selected from the combination of more than two of the above, the ratio of the aprotic polar solvent to the aprotic polar solvent can be any ratio. The aprotic polar solvent is usually used in an amount that can dissolve the starting materials to be reacted.
In the synthesis method of the invention, the hydrogen sulfide donor reagent can be 5-p-hydroxyphenyl-1, 2-dithiole-3-thione (ADT-OH), (R) -lipoic acid (R-lipoic acid) or 4-hydroxythiobenzamide (TBZ), and the structural formulas of the reagents are respectively shown as follows:
in the synthesis method, the reaction of glycyrrhetinic acid, α, omega-dibromoalkane and alkali is preferably carried out at 40 ℃ or below, the applicant finds in experiments that when the reaction is carried out at 20-40 ℃, higher yield can be obtained in a shorter time with fewer side reactions, the reaction of the compound 1, the hydrogen sulfide donor reagent and the alkali is carried out at 65 ℃ or below, more preferably at 35-65 ℃, so that higher yield can be obtained in a shorter time, and the generation of byproducts is reduced as much as possible.
in the synthesis method, the ratio of the glycyrrhetinic acid to the α, omega-dibromoalkane to the alkali is 1: 1-5: 0.5-3, and the ratio of the compound 1 to the hydrogen sulfide donor reagent to the alkali is 1: 1-3: 1-5.
The applicant has found that the addition of the catalyst potassium iodide (KI) in the reaction of compound 1, hydrogen sulfide donor reagent and base further improves the yield of the target compound. The addition amount of the potassium iodide is 0.1-1 time of the amount of the compound 1.
Compared with the prior art, the invention provides a series of glycyrrhetinic acid-hydrogen sulfide donor reagent derivatives with novel structures and a synthesis method thereof, and meanwhile, the applicant also considers the inhibitory activity of the derivatives on liver cancer tumor cell strains and chronic myelogenous leukemia cells, and the results show that most of the compounds have certain inhibitory activity on chronic myelogenous leukemia cells K562, and are expected to be used for preparing corresponding antitumor drugs and drugs for treating chronic myelogenous leukemia.
Detailed Description
The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.
The glycyrrhetinic acid-hydrogen sulfide donor reagent derivative with the structure shown in the general formula (I) is synthesized according to the following synthetic route:
wherein:
the alpha, omega-dibromoalkane can be 1, 2-dibromoethane, 1, 3-dibromopropane, 1, 4-dibromobutane, 1, 5-dibromopentane, 1, 6-dibromohexane, 1, 7-dibromoheptane or 1, 8-dibromooctane;
the aprotic polar solvent may be N, N-dimethylformamide, toluene or pyridine;
the base can be potassium carbonate, triethylamine, sodium carbonate, sodium bicarbonate, potassium bicarbonate or cesium carbonate;
the hydrogen sulfide donor agent may be 5-p-hydroxyphenyl-1, 2-dithiole-3-thione (ADT-OH), (R) -lipoic acid (R-lipoic acid) or 4-hydroxythiobenzamide (TBZ), and the structural formulas thereof are respectively as follows:
n in the compound 1 and the compound 2 is 2-8;
r in the compound 2 is
Example 1: synthesis of Compound 1a
Glycyrrhetinic acid (500mg,1.06mmol) was dissolved in anhydrous DMF (5mL), and 1, 6-dibromoethane (2.43mL,5.3mmol) and K were added2CO3(146.28mg,1.06mmol), and reacted at 30 ℃ for 24 h. The solvent was evaporated under reduced pressure, the residue was dispersed in ethyl acetate (50mL), washed with HCl (1N), water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V)PE:VEA2:1) to give compound 1a (457mg, 75%, white solid).
Yield:457mg,75％,white solid；Rf＝0.461(Petroluem ether:EtOAc＝2:1).M.p 190-192℃.1H NMR(500MHz,CDCl3)δ(ppm):5.69(s,1H,12-H),4.41(dd,J＝28.0,5.9Hz,2H,OCH2),3.53(t,J＝5.7Hz,2H,OCH2),3.21(dd,J＝11.0,5.2Hz,1H,3-H),2.83-2.71(m,1H,18-H),2.32(s,1H),2.21-0.63(m,20H),1.35,1.17,1.12,1.11,0.99,0.80and0.79(7s,each 3H,7×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.2,169.2,128.8,78.9,63.9,61.9,55.1,48.3,45.5,44.3,43.3,41.0,39.2,37.8,37.2,32.9,32.0,31.2,29.2,28.6,28.2,27.4,26.6,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcdfor C32H50BrO4,577.2893；found 577.2873.
Example 2: synthesis of Compound 1b
Glycyrrhetinic acid (500mg,1.06mmol) was dissolved in anhydrous DMF (5mL), and 1, 8-dibromobutane (2.94mL,5.3mmol) and K were added2CO3(146.28mg,1.06mmol), and reacted at 30 ℃ for 24 h. The solvent was evaporated under reduced pressure, the residue was dispersed in ethyl acetate (50mL), washed with HCl (1N), water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V)PE:VEA2:1) to give compound 1b (532mg, 83%, white solid).
Yield:532mg,83％,white solid；Rf＝0.515(Petroluem ether:EtOAc＝2:1).M.p 82-84℃.1H NMR(500MHz,CDCl3)δ(ppm):5.61(s,1H,12-H),4.12(t,J＝6.3Hz,2H,OCH2),3.43(t,J＝6.5Hz,2H,OCH2),3.21(dd,J＝11.1,5.1Hz,1H,3-H),2.77(d,J＝13.5Hz,1H,18-H),2.32(s,1H),2.13-0.61(m,24H),1.35,1.14,1.11,1.10and 0.98(5s,each 3H,5×CH3),0.79(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.5 169.3,128.6,78.8,63.5,61.9,55.0,48.5,45.5,44.1,43.3,41.1,39.2,37.8,37.2,33.1,32.8,31.9,31.2,29.4,28.6,28.2,27.4,26.5,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcd for C34H54BrO4,605.3206；found 605.3188.
Example 3: synthesis of Compound 1c
Glycyrrhetinic acid (1.0g,2.12mmol) was dissolved in anhydrous DMF (5mL), and 1, 6-dibromohexane (1.62mL,10.62mmol), K were added2CO3(293.0mg,2.12mmol), and reacted at 30 ℃ for 24 h. The solvent was evaporated under reduced pressure, the residue was dispersed in ethyl acetate (50ml), which was washed successively with HCl (1N), water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V)PE:VEA2) to give compound 1c (929mg, 69%, white solid).
Yield:929mg,69％,white solid；Rf＝0.452(Petroluem ether:EtOAc＝5:2).M.p 102-104℃.1H NMR(500MHz,CDCl3)δ(ppm):5.61(s,1H,12-H),4.08(m,2H,OCH2),3.39(m,2H,CH2-Br),3.20(dd,J＝11.1,5.2Hz,1H,3-H),2.76(d,J＝13.5Hz,1H,18-H),2.32(s,1H,10-H),2.09-0.69(m,35H),1.35,1.13,1.11,1.10and 0.98(5s,each 3H,5×CH3),0.79(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.6,169.4,128.6,61.9,78.8,64.4,55.0,48.5,45.5,44.1,43.3,41.2,39.2,37.9,37.2,33.9,32.9,32.7 31.9,31.2,28.7,28.5,28.2,27.8,27.4,26.6,26.5,25.4,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcd for C36H58BrO4,633.3519；found633.3525.
Example 4: synthesis of Compound 1d
Glycyrrhetinic acid (1.0g,2.12mmol) was dissolved in anhydrous DMF (5mL), and 1, 8-dibromooctane (1.62mL,10.62mmol) and K were added2CO3(293.0mg,2.12mmol), and reacted at 30 ℃ for 24 h. The solvent was evaporated under reduced pressure, the residue was dispersed in ethyl acetate (50mL), washed with HCl (1N), water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V)PE:VEA2) to give compound 1d (984mg, 62%, white solid).
Yield:984mg,62％,white solid；Rf＝0.500(Petroluem ether:EtOAc＝5:2).M.p 67-69℃.1H NMR(500MHz,CDCl3)δ(ppm):5.62(s,1H,12-H),4.07(m,2H,OCH2),3.39(m,2H,CH2-Br),3.21(dd,J＝11.1,5.2Hz,1H,3-H),2.77(d,J＝13.6Hz,1H,18-H),2.32(s,1H,10-H),2.10-0.69(m,35H),1.35,1.13,1.12,1.11and 0.99(5s,each 3H,5×CH3),0.79(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.3,176.6,169.4,128.6,78.9,64.6,61.9,55.1,48.5,45.5,44.1,43.3,41.2,39.2,37.9,34.1,37.2,32.9,31.9,31.3,29.1,28.7,28.8,28.7,28.6,28.3,28.2,27.4,26.6,26.5,26.0,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcd for C38H62BrO4,661.3831；found 661.3836.
Example 5: synthesis of Compound 2a
Compound 1a (250mg,0.43mmol) was dissolved in DMF (5mL), and (R) -lipoicic acid (88.58mg,0.43mmol), K were added2CO3(178.02mg,1.29mmol), and reacted at 50 ℃ for 24 h. The residue was dispersed in ethyl acetateWashing the ester (50mL) with HCl (1N), water and saturated brine in this order, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating by column chromatography (V)PE:VEA2:1) to give compound 2a (231mg, 76%, light yellow solid).
Yield:231mg,76％,yellow solid；Rf＝0.490(Petroluem ether:EtOAc＝2:1).M.p 64-66℃.1H NMR(500MHz,CDCl3)δ(ppm):5.62(s,1H,12-H),4.41-4.18(m,4H,2×OCH2),3.52(dd,J＝8.2,6.4Hz,1H,3-H),3.25-2.98(m,3H),2.75(d,J＝13.5Hz,1H,18-H),2.44(s,1H),2.33(dd,J＝14.7,7.2Hz,3H),2.14-0.60(m,26H),1.34,1.13,1.10,1.09,0.97,0.78and 0.77(7s,each 3H,7×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.1,176.2,173.3,169.2,128.5,78.8,62.3,61.9,56.4,55.0,48.4,45.5,44.1,43.3,41.1,40.3,39.2,38.6,37.8,37.2,34.6,34.0,32.8,31.9,31.2,28.8,28.7,28.3,28.2,27.3,26.5,24.6,23.5,18.8,17.6,16.4,15.7,14.3.HRMS(ESI)m/z:[M+H]+calcdfor C40H62ClO6S2,737.3676；found 737.3696.
Example 6: synthesis of Compound 2b
Compound 1b (250mg,0.41mmol) was dissolved in DMF (5mL) F and (R) -lipoicic acid (85.12mg,0.41mmol), K were added2CO3(169.74mg,1.23mmol), and reacted at 50 ℃ for 24 h. The residue was dispersed in ethyl acetate (50mL), washed successively with HCl (1N), water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V)PE:VEA2:1) to give compound 2b (190mg, 63%, light yellow solid).
Yield:190mg,63％,yellow solid；Rf＝0.431(Petroluem ether:EtOAc＝2:1).M.p 60-62℃.1H NMR(500MHz,CDCl3)δ(ppm):5.60(s,1H,12-H),4.09(m,4H,2×OCH2),3.54(dd,J＝8.2,6.4Hz,1H,3-H),3.21-3.02(m,3H),2.75(dd,J＝13.3,3.3Hz,1H,18-H),2.45(s,1H),2.30(dd,J＝9.8,4.7Hz,3H),2.15-0.61(m,30H),1.34,1.13,1.10,1.09and0.98(5s,each 3H,5×CH3),0.78(s,6H,2×CH3).13C NMR(125MHz,CDCl3)δ(ppm):200.2,176.5,173.6,169.3,128.6,78.8,63.9,61.9,56.4,55.0,48.5,45.5,44.1,43.3,41.1,40.3,39.2,38.6,37.8,37.2,34.7,34.1,32.8,31.9,31.2,28.8,28.7,28.5,28.2,27.4,26.6,26.5,25.6,25.5,24.7,23.5,18.8,17.6,16.5,15.7.HRMS(ESI)m/z:[M+H]+calcdfor C42H66ClO6S2,765.3989；found 765.4008.
Example 7: synthesis of Compound 2c
Compound 1c (500mg,0.79mmol) was dissolved in DMF (5mL), and (R) -lipoicic acid (163.0mg,0.79mmol), K were added2CO3(327.58mg,2.37mmol) and reacted at 50 ℃ for 24 h. The residue was dispersed in ethyl acetate (50mL), washed successively with HCl (1N), water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V)PE:VEA3:1) to give compound 2c (402mg, 67%, light yellow solid).
Yield:402mg,67％,yellow solid；Rf＝0.339(Petroluem ether:EtOAc＝3:1).M.p 51-53℃.1H NMR(400MHz,CDCl3)δ(ppm):5.60(s,1H,12-H),4.05(m,4H,2×OCH2),3.54(dd,J＝8.0,6.5Hz,1H,3-H),3.25-3.03(m,3H),2.75(dd,J＝10.1,3.4Hz,1H,18-H),2.42(m,1H),2.29(m,2H),2.12-0.58(m,36H),1.35(s,3H,CH3),1.12–1.04(m,9H,3×CH3),0.97(s,3H,CH3),0.77(s,6H,2×CH3).13C NMR(100MHz,CDCl3)δ(ppm):200.2,176.5,173.6,169.3,128.6,78.8,64.4,61.9,56.4,55.0,48.5,45.5,44.1,43.3,41.2,40.3,39.2,38.5,37.8,37.2,34.7,34.2,32.8,31.9,31.2,28.6,28.2,27.4,26.5,25.8,25.6,24.8,23.5,18.8,17.6,16.4,15.7.HRMS(ESI)m/z:[M+H]+calcd for C44H71O6S2,759.4692；found759.4696.
Example 8: synthesis of Compound 2d
Compound 1d (500mg,0.76mmol) was dissolved in DMF (5mL), and (R) -lipoicid (156.81mg,0.76mmol) and K were added2CO3(315.12mg,2.28mmol), and reacted at 50 ℃ for 24 h. The residue was dispersed in ethyl acetate (50mL), washed successively with HCl (1N), water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V)PE:VEA3:1) to give compound 2d (475mg, 80% as pale yellow solid).
Yield:475mg,80％,yellow solid；Rf＝0.578(Petroluem ether:EtOAc＝3:1).M.p 52-54℃.1H NMR(400MHz,CDCl3)δ(ppm):5.60(s,1H,H-12),4.13-3.97(s,4H,2×OCH2),3.53(m,1H,3-H),3.27(m,3H),2.74(d,J＝13.5Hz,1H,18-H),2.42(dd,J＝12.5,6.2Hz,1H),2.28(dd,J＝13.7,6.3Hz,3H),2.10-0.60(m,40H),1.12-1.05(m,9H,2×CH3),0.96(s,6H,2×CH3),0.77(s,6H,2×CH3).13C NMR(100MHz,CDCl3)δ(ppm):200.2,176.5,173.6,169.3,128.5,78.7,64.5,61.9,56.4,55.0,48.4,45.4,44.0,43.3,41.1,40.2,39.2,38.5,37.8,37.1,34.6,34.1,32.8,31.9,31.2,29.1,28.8,28.7,28.6,28.5,28.2,27.4,26.5,25.9,24.8,23.5,18.7,17.5,16.4,15.7.HRMS(ESI)m/z:[M+H]+calcd forC46H75O6S2,787.5005；found 787.5019.
Example 9: synthesis of Compound 2e
Compound 1c (500mg,0.79mmol) was dissolved in DMF (5mL) and ADT-OH (178.57mg,0.79mmol), K were added2CO3(327.58mg,2.37mmol), KI (13.28mg,0.08mmol), and reacted at 65 ℃ for 24 h. The residue was dispersed in ethyl acetate (50mL), washed successively with HCl (1N), water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V)PE:VEA3:1) to give compound 2e (126mg, 21%, orange solid).
Yield:126mg,21％,orange solid；Rf＝0.352(Petroluem ether:EtOAc＝3:1).M.p 92-94℃.1H NMR(400MHz,CDCl3)δ(ppm):7.60(d,J＝8.8Hz,2H,Ar-H),7.39(s,1H,Ar-H),6.96(d,J＝8.8Hz,2H,Ar-H),5.63(s,1H,12-H),4.22-3.97(m,4H,2×OCH2),3.23(dd,J＝10.9,5.3Hz,1H,3-H),2.79(d,J＝13.5Hz,1H,18-H),2.34(s,1H,9-H),2.13-0.69(m,29H),1.19-1.09(m,9H,3×CH3),1.01(s,6H,2×CH3),0.81(s,6H,2×CH3).13CNMR(100MHz,CDCl3)δ(ppm):215.1,200.3,176.6,173.3,169.5,162.6,134.6,128.7,128.6,124.0,115.6,78.8,68.3,64.4,61.9,55.0,48.6,45.5,44.1,43.3,41.2,39.2,37.8,37.2,32.9,31.9,31.2,29.0,28.8,28.7,28.5,28.2,27.4,26.54,26.51,25.9,25.7,23.5,18.8,17.6,16.5,15.7.HRMS(APCl)m/z:[M+H]+calcd for C45H63O5S3,779.3838；found 779.3820.
Example 10: synthesis of Compound 2f
Compound 1d (500mg,0.76mmol) was dissolved in DMF (5mL) and ADT-OH (169.74mg,0.76 m) was addedmol)、K2CO3(315.12mg,2.28mmol), KI (13.28mg,0.08mmol), and reacted at 65 ℃ for 24 h. The residue was dispersed in ethyl acetate (50mL), washed successively with HCl (1N), water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V)PE:VEA3:1) to give compound 2f (118mg, 19%, orange solid).
Yield:118mg,19％,orange solid；Rf＝0.369(Petroluem ether:EtOAc＝3:1).M.p 87-89℃.1H NMR(400MHz,CDCl3)δ(ppm):7.60(d,J＝8.8Hz,2H,Ar-H),7.39(s,1H),6.96(d,J＝8.8Hz,2H,Ar-H),5.64(s,1H,12-H),4.14-3.98(m,4H,2×OCH2),3.22(dd,J＝10.7,5.3Hz,1H,3-H),2.78(d,J＝13.5Hz,1H,18-H),2.34(s,1H,9-H),2.17-0.64(m,33H),1.16-1.10(m,9H,3×CH3),1.00(s,3H,CH3),0.80(s,6H,2×CH3).13C NMR(100MHz,CDCl3)δ(ppm):215.2,200.3,176.6,173.3,169.4,162.7,134.6,128.7,128.6,124.0,115.6,78.8,68.5,64.6,61.9,55.1,48.5,45.5,44.1,43.3,41.2,39.2,37.9,37.2,32.9,31.9,31.3,29.3,29.2,29.1,28.7,28.5,28.2,27.4,26.6,26.5,26.0,26.0,23.5,18.8,17.6,16.5,15.7.HRMS(APCl)m/z:[M+H]+calcd forC47H67O5S3,807.4151；found 807.4118.
Example 11: synthesis of Compound 2g
Compound 1c (250mg,0.39mmol) was dissolved in DMF (5mL), and TBZ (60.35mg,0.39mmol), K were added2CO3(28mg,0.2mmol), KI (6.30mg,0.04mmol), at 35 ℃ for 12 h. The residue was dispersed in ethyl acetate (50mL), washed successively with HCl (1N), water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V)PE:VEA3:1) to give compound 2g (91mg, 32%, light yellow solid).
Yield:91mg,32％,yellow solid；Rf＝0.267(Petroluem ether:EtOAc＝3:1).M.p 119-120℃.1H NMR(500MHz,DMSO-d6)δ(ppm):9.30(s,1H,NH)，8.23(s,1H,NH),7.48(d,J＝8.8Hz,2H,Ar-H),6.99(d,J＝8.9Hz,2H,Ar-H),5.40(s,1H,12-H),4.02–3.96(m,4H,2×OCH2),2.98(d,J＝4.5Hz,1H,3-H),2.55(d,J＝13.2Hz,1H,18-H),2.30(s,1H),2.18–0.63(m,28H),1.08,0.89and 0.72(3s,each 3H,3×CH3,1.00and 0.67(2s,each 6H,4×CH3).13C NMR(125MHz,DMSO-d6)δ(ppm):199.1,191.7,175.9,169.5,161.6,134.2,126.4,120.9,115.0,76.6,67.8,63.9,61.2,54.1,48.1,44.9,43.6,42.9,37.4,36.7,32.1,31.6,30.4,29.1,28.7,28.6,28.5,28.32,28.28,28.2,27.8,27.0,26.1,25.8,25.6,25.4,23.0,22.2,18.4,17.2,16.2,16.1.HRMS(ESI)m/z:[M+Na]+calcd for C43H64NO5S,706.4505；found 706.4500.
Example 12: synthesis of Compound 2h
Compound 1d (250mg,0.38mmol) was dissolved in DMF (5mL), and TBZ (57.80mg,0.38mmol), K were added2CO3(28mg,0.20mmol), KI (6.30mg,0.04mmol), at 35 ℃ for 12 h. The residue was dispersed in ethyl acetate (50mL), washed successively with HCl (1N), water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (V)PE:VEA3:1) to give compound 2h (107mg, 39%, light yellow solid).
Yield:107mg,39％,yellow solid；Rf＝0.206(Petroluem ether:EtOAc＝3:1).M.p 117-119℃.1H NMR(500MHz,DMSO-d6)δ(ppm):9.63(s,1H,NH),9.31(s,1H,NH),7.94(d,J＝8.9Hz,2H,Ar-H),6.91(d,J＝8.9Hz,2H,Ar-H),5.42(s,1H,12-H),4.01(m,4H,2×OCH2),3.01(dd,J＝11.4,4.4Hz,1H,3-H),2.58(s,1H,18-H),2.31(s,1H),2.15-0.64(m,32H),1.09,0.90and 0.73(3s,each 3H,3×CH3),1.02and 0.68(2s,each 6H,4×CH3).13CNMR(125MHz,DMSO-d6)δ(ppm):199.0,198.5,175.8,169.4,161.4,131.1,129.5,127.4,113.4,76.6,67.7,63.9,61.2,59.8,54.1,48.1,44.9,43.6,42.9,37.4,36.7,32.1,31.5,30.4,28.5,28.2,27.8,27.0,26.1,25.8,25.4,25.2,23.0,20.8,18.4,16.2,16.0,14.4.HRMS(ESI)m/z:[M+Na]+calcd forC45H68NO5S,734.4818；found 734.4816.
Example 13: synthesis of Compound 2a
Example 5 was repeated except that: toluene for DMF and cesium carbonate for K2CO3And the temperature was changed to 40 ℃ for 12 h.
The resulting product (228mg, 75%, light yellow solid) was identified by nuclear magnetism as compound 2a, which has the following structural formula:
example 14: synthesis of Compound 2b
Example 6 was repeated except that: pyridine is used for replacing DMF, and potassium bicarbonate is used for replacing K2CO3And 0.5 times the amount of the compound 1b substance as the catalyst KI was added.
The resulting product (166mg, 55%, light yellow solid) was identified by nuclear magnetism as compound 2b, which has the following structural formula:
example 15: synthesis of Compound 2e
Example 9 was repeated, except that: toluene for DMF and sodium carbonate for K2CO3And the residue was dispersed in dichloromethane without addition of catalyst KI.
The resulting product (72mg, 12%, orange solid) was identified by nuclear magnetism as compound 2e, which has the following structural formula:
example 16: synthesis of Compound 2f
Example 10 was repeated except that: using a combination of toluene and DMF (consisting of toluene and DMF in a volume ratio of 1: 1) to replace DMF, and using triethylamine to replace K2CO3And the residue was dispersed in diethyl ether without addition of catalyst KI.
The resulting product (62mg, 10%, orange solid) was identified by nuclear magnetism as compound 2f, which has the following structural formula:
example 16: synthesis of Compound 2h
Example 12 was repeated except that: using a combination of pyridine and toluene (consisting of picoline and toluene in a volume ratio of 1: 5) in place of DMF, and using sodium bicarbonate in place of K2CO3And no catalyst KI is added.
The resulting product (49mg, 18%, light yellow solid) was identified by nuclear magnetism as compound 2h, which is shown by the following structural formula:
the applicant experimented the proliferation inhibition activity of the compounds 2 a-2 h of the invention on human liver cancer tumor cell strains and chronic myelogenous leukemia cells:
1. cell lines and cell cultures
3 human cell strains such as human liver cancer cell BEL-7402, chronic myelogenous leukemia cell K562 and human normal liver cell L-O2 are selected for the experiment.
All cell lines were cultured in RPMI-1640 medium containing 10 wt% calf blood, 100U/mL penicillin and 100U/mL streptomycin, and placed at 37 ℃ in a volume concentration of 5% CO2Culturing in an incubator.
2. Preparation of test Compounds
The purity of the used test drug is more than or equal to 95 percent, the DMSO stock solution is diluted by physiological buffer solution to prepare 200 mu mol/L final solution, wherein the final concentration of the cosolvent DMSO is less than or equal to 1 percent, and the inhibition degree of the compound to the growth of various tumor cells under the concentration is tested.
3. Cell growth inhibition assay (MTT method)
(1) Taking tumor cells in logarithmic growth phase, digesting by trypsin, preparing 5000/mL cell suspension by using culture solution containing 10% calf serum, inoculating 190 mu L of the cell suspension into a 96-hole culture plate, and enabling the cell density to be detected to reach 1000-10000 holes (the edge holes are filled with sterile PBS);
(2)5％CO2incubating for 24h at 37 ℃ until a cell monolayer is paved on the bottom of each well, adding 10 mu L of medicine with a certain concentration gradient into each well, and arranging 4 compound wells in each concentration gradient;
(3)5％CO2incubating at 37 ℃ for 48 hours, and observing under an inverted microscope;
(4) add 10. mu.L of MTT solution (5mg/mL PBS, i.e., 0.5% MTT) to each well and continue culturing for 4 h;
(5) terminating the culture, carefully removing the culture solution in the wells, adding 150 μ L of DMSO into each well to sufficiently dissolve formazan precipitate, mixing uniformly with an oscillator, and measuring the optical density of each well with a microplate reader at a wavelength of 570nm and a reference wavelength of 450 nm;
(6) simultaneously, a zero setting hole (culture medium, MTT, DMSO) and a control hole (cells, a drug dissolving medium with the same concentration, a culture solution, MTT, DMSO) are arranged.
(7) The number of living cells was judged from the measured optical density values (OD values), and the larger the OD value, the stronger the cell activity. Using the formula:
the inhibition rate of the compound on the growth of each cell line was calculated, and the results are shown in table 1 below.
Table 1: IC of each compound on different cell lines50Value (μ M)
Note: the data are the average of 3 experiments, and Nd indicates that the test compound has no inhibitory activity on the cells.
Claims (10)
1. A glycyrrhetinic acid-hydrogen sulfide donor reagent derivative having a structure represented by the following general formula (I):
wherein,
when R isWhen n is 8;
when R isWhen n is 2, 4, 6 or 8;
when R isWhen n is 6 or 8.
2. the synthesis method of the glycyrrhetinic acid-hydrogen sulfide donor reagent derivative of claim 1 is characterized by taking glycyrrhetinic acid, α, omega-dibromoalkane and alkali to react in an aprotic polar solvent to obtain a compound 1, taking the compound 1, a hydrogen sulfide donor reagent and alkali to react in the aprotic polar solvent to obtain a target crude product, wherein the reaction is carried out under the condition of heating or not, and the structural formula of the compound 1 is as follows:
wherein n is 2, 4, 6 or 8.
3. The method of synthesis according to claim 2, characterized in that: the method comprises the following steps:
1) reacting glycyrrhetinic acid, α, omega-dibromoalkane and alkali in an aprotic polar solvent, removing the solvent from the obtained reactant, dispersing the residue in ethyl acetate, dichloromethane or diethyl ether, washing, drying with anhydrous sodium sulfate, filtering, collecting the filtrate, and concentrating the filtrate to obtain a compound 1;
2) taking the compound 1, a hydrogen sulfide donor reagent and alkali to react in an aprotic polar solvent, removing the solvent from the obtained reactant, dispersing the residue in ethyl acetate, dichloromethane or ether, washing, drying with anhydrous sodium sulfate, filtering, collecting the filtrate, and concentrating the filtrate to obtain a crude product of the target product.
4. A synthesis method according to claim 2 or 3, characterized in that: the obtained compound 1 is purified by silica gel thin layer chromatography or silica gel column chromatography and then used for subsequent operations.
5. A synthesis method according to claim 2 or 3, characterized in that: further comprises the step of purifying the crude target product: specifically, the prepared crude target product is subjected to silica gel thin-layer chromatography or silica gel column chromatography to obtain a purified target product.
6. the synthesis method according to claim 2 or 3, wherein the α, ω -dibromoalkane is 1, 2-dibromoethane, 1, 3-dibromopropane, 1, 4-dibromobutane, 1, 5-dibromopentane, 1, 6-dibromohexane, 1, 7-dibromoheptane or 1, 8-dibromooctane.
7. A synthesis method according to claim 2 or 3, characterized in that: the alkali is potassium carbonate, triethylamine, sodium carbonate, sodium bicarbonate, potassium bicarbonate or cesium carbonate; the aprotic polar solvent is one or the combination of more than two of N, N-dimethylformamide, toluene and pyridine.
8. A synthesis method according to claim 2 or 3, characterized in that: the hydrogen sulfide donor reagent is 5-p-hydroxyphenyl-1, 2-dithiole-3-thione, (R) -lipoic acid or 4-hydroxythiobenzamide.
9. A synthesis method according to claim 2 or 3, characterized in that: in the reaction of compound 1, hydrogen sulfide donor reagent and base, potassium iodide was added as a catalyst.
10. Use of the glycyrrhetinic acid-hydrogen sulfide donor reagent derivative of claim 1 in a medicament for the treatment of chronic myelogenous leukemia.
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